This invention relates generally to devices used in fluid deposition and inspection and more particularly relates to an apparatus for depositing and selectively inspecting chemical and biological fluid arrays.
In the fields of chemistry, biochemistry, and molecular biology, there is a need to improve capabilities for carrying out large numbers of reactions using small quantities of materials in a short time period. As a result, there is a significant and growing interest in employing array technologies where the arrays comprise an ever increasing number of distinct features on a relatively small substrate.
Many methods for making arrays of biological materials are currently available. Generally, DNA arrays are fabricated on a solid substrate by deposition of whole DNA oligomers or complementary DNA or by in-situ synthesis of DNA oligomers. Specific methods for fabricating biological arrays are summarized in international patent publication WO 95/35505. This reference discusses the xe2x80x9cdot blotxe2x80x9d technique in which a vacuum manifold transfers a number of DNA samples from circular wells to a porous membrane. In addition, DNA sequences can also be synthesized by using a photolithographic technique as discussed in U.S. Pat. No. 5,445,934 to Fodor et al., and by using a capillary dispenser tapping technique as discussed in U.S. Pat. No. 5,807,522 to Brown et al. All of these techniques suffer from inherent limitations that reduce the capacity for producing arrays accurately and reliably.
Arrays may be prepared by a variety of methods employed in the printing industry that do not suffer from the aforementioned limitations. U.S. patent applications Ser. Nos. 09/150,504 and 09/150,507 describe forming biomolecular arrays by adaptations of devices employed in the printing industry and, particularly, of inkjet printheads and of automated devices for moving a printhead over a print surface and for depositing fluids at desired locations on the surface. Other uses of inkjet printing devices to dispense biochemical agents such as proteins and nucleic acids are suggested or described in, for example, U.S. Pat. Nos. 5,658,802; 5,338,688; 5,700,637; 5,474,796; 4,877,745; and 5,449,754. In essence, inkjet printing processing as applied to array fabrication involves feeding fluid composition from a reservoir into a dispensing chamber of an inkjet printhead and providing a stimulus repeatedly to cause the fluid composition to issue from a nozzle or orifice toward a substrate at desired locations, thus forming an array of features.
It is important to deposit uniform features, particularly when automated array fabrication techniques are used. In co-pending, commonly assigned U.S. patent application Ser. No. 09/150,504, filed Sep. 9, 1998, for xe2x80x9cMethod and Apparatus for Making Nucleic Acid Arraysxe2x80x9d by Caren et al., an apparatus is described that can be used to deposit an array of uniform nucleic acid features on a substrate surface. The apparatus can form arrays by depositing droplets in the picoliter range on substrates having a rectangular surface of various sizes, 125 mm by 80 mm for example as described in the application, resulting in an enormous number of features deposited on a single substrate surface. In addition, after a feature is deposited, there is a need to inspect each feature of the array for characteristics such as size, shape, position and the like.
The use of digital video cameras for inspection of deposited materials on substrates is generally well known. U.S. Pat. No. 5,724,437 to Bucher et al., for example, describes a device for parallel image inspection and ink control on a printed product. In addition, camera-based inspection systems for arrays are widely known in the field of semiconductor processing. U.S. Pat. No. 5,882,720 to Legault et al. describes an inspection system that automatically monitors pads of materials deposited on a surface of a workpiece using an inspection system having charged couple device. U.S. Pat. No. 5,812,268 to Jackson et al. describes a grid array inspection system and method where the grid array is placed upon a fixture above a motion control table and scanned with a three-dimensional scanner. U.S. Pat. No. 4,929,845 to Amir et al. describes the use of a line scan camera to inspect a circuit board for proper placement of components to be soldered prior to soldering. In the biological field, U.S. Pat. No. 5,629,169 to Izraelevitz et al. describes a method of estimating effectiveness of antibiotics by analyzing the digital image of a plurality of antibiotic disks positioned a substrate containing a population of test organisms.
One possible way to inspect an array is to wait until after the entire array has been deposited, then digitize the image of the entire substrate, and finally process the data for each feature. However, as the number of features deposited in an array increases with improving technology, the amount of memory needed to store an entire array image becomes enormous. Generally, waiting for an array to be completed for imaging is an inefficient use of time. In certain cases, multiple deposition cycles or passes, i.e., the successive deposition of subarrays, are needed to deposit all the features in an array. In such cases, subarrays may be arranged in a manner such that a long time interval may pass before adjacent features are deposited. When the goal of inspection is to image the features immediately following or soon after deposition of liquid-containing features before the features are dry, multiple inspection cycles may be required to inspect features within a subarray with each inspection cycle or pass. Thus, there is a need to acquire and analyze images of deposited array features as features are being deposited.
Accordingly, it is an object of the present invention to overcome the above-mentioned disadvantages of the prior art by providing a new apparatus to deposit a pattern of features on a surface of a substrate and to acquire images of the features.
It is another object of the invention to provide such an apparatus to improve efficient use of time and computing resources in inspecting the features on a substrate by reducing the imaging data acquired for inspection of features in an array.
It is still another object of the invention to provide such an apparatus employing a line scan camera to acquire and inspect images of a pattern of features.
It is a further object of the invention to provide such an apparatus to deposit features in an array to allow for controlled activation of a camera to minimize the acquisition of unnecessary imaging data.
It is a further object of the invention to provide such a means for a computerized controller to active a camera based on reading of a image or data file.
It is still a further object of the invention to provide such an apparatus to inspect a pattern of features on a substrate while the pattern is being deposited.
It is another object of the invention to provide such an apparatus to detect deficiencies in array fabrication and to generate a signal to flag the deficiency.
It is still another object of the invention to provide such an apparatus to control the quality of features deposited on a substrate during automated array fabrication.
Additional objects, advantages and novel features of the invention will be set forth in part in the description which follows, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention.
In one aspect, then, the present invention relates to an apparatus for producing and inspecting a plurality of features in a pattern on a portion of a surface of a substrate. The apparatus comprises a printhead for depositing a fluid to form a plurality of features in a pattern on the surface of the substrate and an image acquisition system for imaging the deposited features. Also provided is a printhead controller for positioning and activating the inkjet printhead to deposit sequentially the plurality of features in the pattern. The image acquisition system comprises a camera controlled by a camera controller such that the camera acquires images corresponding to a first portion of the surface on which the features should have been deposited and less than all of a second portion of the surface that is nominally featureless. Preferably, the camera controller and printhead controller are coupled such that activation of the printhead by the printhead controller is accompanied with imaging by the camera. Corresponding imaging may or may not occur simultaneously. In addition, it is preferred that the camera and printhead are respectively situated such that an induced movement of the printhead relative to the substrate results in a substantially identical corresponding movement of the camera relative to the substrate.
In another aspect, the invention as described above further comprises means for comparing an image acquired by the camera with a predetermined standard to produce a signal. The signal can alert an operator of the apparatus of a defectively deposited feature so that experimental data derived from such features are discarded. Alternatively, the signal can trigger corrective action by the printhead controller to adjust deposition parameters accordingly, such that features remain within specified limits.
In a further aspect, the invention is directed to an apparatus for inspecting a plurality of features in a pattern on a portion of a surface of a substrate. The apparatus comprises a camera for imaging the surface of the substrate and a controller for positioning and activating the camera to acquire images corresponding to the portion of the surface on which the features have been deposited and less than all of the portion of the nominally featureless portion of the surface. The apparatus optionally comprises means for comparing an image acquired by the camera with a predetermined standard to produce a signal. The signal may be used to alert an operator of inadequately formed features.